AFIRE Supports Rivaroxaban Monotherapy in A-fib Patients With Stable CAD

PARIS, France—In patients with atrial fibrillation and stable CAD who are at least a year out from any revascularization procedures, rivaroxaban (Xarelto; Bayer/Janssen) monotherapy is the better choice compared with rivaroxaban plus antiplatelet therapy, the AFIRE trial indicates.

Monotherapy was noninferior in terms of a composite stroke, systemic embolism, MI, unstable angina requiring revascularization, or all-cause death through 2 years of follow-up (4.14% vs 5.75% per patient-year; P < 0.001 for noninferiority), according to Satoshi Yasuda, MD, PhD (National Cerebral and Cardiovascular Center, Osaka, Japan).

Keeping to a single agent, however, carried a significantly lower risk of ISTH-defined major bleeding (1.62% vs 2.76% per patient-year; P = 0.01 for superiority), he reported here at the European Society of Cardiology Congress 2019.

Moreover, the risk of all-cause death was significantly reduced with monotherapy (1.85% vs 3.37%), reflecting lower rates of both cardiovascular and noncardiovascular deaths. That difference led the trial’s data and safety monitoring committee to stop the study early.

The findings, which also were published online in the New England Journal of Medicine, “support the general concept that rivaroxaban monotherapy without antiplatelet therapy is the better approach for patients with AF and stable CAD,” Yasuda said during a press conference.

Commenting for TCTMD, Dominick Angiolillo, MD, PhD (University of Florida College of Medicine – Jacksonville), said AFIRE “for the first time in a trial with a [direct oral anticoagulant] shows that you do not need to combine with aspirin, which is something that happens a lot in clinical practice. And not only that, but if you’re doing it, there’s actually safety concerns, including increased mortality.”

The study was limited by its relatively small size and by the inclusion of only Asian patients, who are more prone to bleeding complications than are Western populations. Thus, the findings can’t be generalized to non-Asians, Angiolillo said. “Having said that, I believe that the findings provide support to some of the recommendations that are described in guidelines both in Europe and the United States, but it would be nice for us to have our own data.”

Filling the Evidence Gap

Guidelines and expert consensus statements currently recommend monotherapy with an oral anticoagulant in patients with A-fib who are at least a year out from PCI or who have stable coronary disease not requiring intervention. But that guidance is not informed by randomized data, and use of combination therapy remains common in practice, Yasuda said.

A prior randomized trial called OAC-ALONE attempted to provide needed evidence in this area, but it was stopped early and had an insufficient number of patients to conclusively evaluate the relative merits of oral anticoagulation alone versus a combination of anticoagulation and single antiplatelet therapy.

Despite also being halted early, the AFIRE trial, conducted at centers across Japan, enrolled three times as many patients as did OAC-ALONE. It included 2,236 patients with A-fib who had a history of PCI or CABG more than a year before randomization or who had angiographically confirmed coronary disease not requiring revascularization. Mean patient age was 74, and 79% were men.

Definitely it speaks to the concept that combining therapies is not a good thing and it can be actually associated with harm. Dominick Angiolillo

Participants were randomized to rivaroxaban monotherapy (at a dose of 10 mg once daily for those with a creatinine clearance of 15 to 49 mL/min or 15 mg for those with a higher creatinine clearance) or rivaroxaban plus a single antiplatelet agent, which could be either aspirin or a P2Y12 inhibitor at the discretion of the treating physician. Most patients (70.2%) received aspirin and 26.8% received a P2Y12 inhibitor, mostly clopidogrel.

Through a median follow-up of 24.1 months, the reduced rate of the primary composite endpoint rivaroxaban monotherapy met criteria for noninferiority in the main analysis and for superiority in a post hoc analysis.

Monotherapy was also associated with reductions in hemorrhagic stroke (0.18% vs 0.60%) and net adverse clinical events (3.90% vs 6.28%), which is a composite of all-cause death, MI, stroke, or major bleeding. Any bleeding and nonmajor bleeding also occurred less frequently in the monotherapy arm.

Serving as a discussant following Yasuda’s presentation Freek Verheugt, MD, PhD (Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands), said the mechanism underlying the advantage for rivaroxaban monotherapy in terms of ischemic outcomes is likely related to reductions in bleeding, which has been correlated with mortality.

Confirmation Needed

But there are some limitations, Verheugt pointed out. He cited the open-label design; the premature end of the study for efficacy, which may overestimate efficacy results; the use of a dose of rivaroxaban that is lower than that used in Western countries, which might underestimate bleeding; and the inclusion of East Asian patients, who are more likely to be poor metabolizers of clopidogrel, which also may have led to underestimation of bleeding.

“Given these caveats, I think the AFIRE trial results may not be applicable for AF patients on another [direct oral anticoagulant] or AF patients on [a vitamin K antagonist]. So we have to be careful,” he said.

In addition, there is a need for another trial with a sufficient number of patients to confirm the results, preferably in non-Asian patients, Verheugt said, noting that a trial called AQUATIC will soon be starting France. The trial will aim to enroll 2,000 patients with A-fib who are taking anticoagulation and who undergo stenting. They will get 1 year of oral anticoagulation plus antiplatelet therapy and will then be randomized to continue that regimen or step down to oral anticoagulation alone.

Although confirmation is needed, Verheugt said the AFIRE results “confirm the EU and US guidelines to quit antiplatelet therapy 1 year after PCI in A-fib patients who are anticoagulated. Stopping at 1 year is safer, it’s more effective than continuation, and most of all, it saves lives.”

Angiolillo said about AFIRE: “Definitely it speaks to the concept that combining therapies is not a good thing and it can be actually associated with harm. The good news is that the finding overall is consistent with guideline recommendations on two sides of the Atlantic, and we’ll just see how practice patterns change, because there’s still a huge uptake of combination therapy after 1 year in the United States.”

In an editorial accompanying the NEJM paper, Richard Becker, MD (University of Cincinnati College of Medicine, OH), says AFIRE and OAC-ALONE together “do add an element of support for current guidelines and underscore the potential effect of direct oral anticoagulants on the pathobiology of coronary artery disease and cardioembolic events in patients with atrial fibrillation, but they fall short of securing level I and class A evidence. Further investigation will be required.”